tbuckley/cabot-search huggingface dataset:
PATH-09. SUBTYPE-ASSOCIATED RNA SPLICING CONTROLLED BY GLIOMA DRIVER MUTATIONS REGULATES GLIOMAGENESIS
Authors: Xiao Song, Tianzhi Huang, Deanna Tiek, Shunichiro Miki, Anshika Goenka, Rebeca Iglesia, Frank Furnari, Bo Hu, Bo Hu
Journal: Neuro-Oncology (2022)

Abstract Dysregulated RNA alternative splicing (AS) is a hallmark of cancer and has been studied in cancers including glioma. However, whether the dysregulated AS and the regulating RNA-binding proteins (RBPs) drive gliomagenesis and the role of glioma driver mutations in shaping the RBP/AS landscape have not been studied. Here we describe two AS-defined glioma subtypes that correlate with IDH1 mutation, tumor grade, and patient prognosis. Oncogenic AS isoforms are exclusively associated with AS subtype 2, IDH1 wild-type gliomas. Modulation of representative AS isoforms or subtype-associated RBPs regulate glioma stem-like cell (GSC) tumorgenicity. With a human induced pluripotent stem cell-derived glioma model system, we demonstrate that specific glioma driver mutations are involved in shaping the subtype-associated AS. Lastly, we target a sub2-associated RBP with anti-sense oligonucleotides to inhibit GSC tumorigenicity. Our data establish relationships between glioma driver mutations and AS programs and identify dysregulated RBP/AS network as a therapeutic vulnerability.
EXTH-52. HARNESSING A B CELL THERAPY TO PROMOTE ANTI-GLIOBLASTOMA HUMORAL RESPONSE
Authors: Brandyn Castro, Mariafausta Fischietti, Andrew Zolp, Junfei Zhao, David Hou, Linh Nguyen, Hanxiao Wan, Peng Zhang, Yu Han, Aurora Lopez-Rosas, Leonidas Platanias, Roger Stupp, Jason Miska, Maciej Lesniak, Catalina Lee-Chang
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) continues to retain its dismal prognosis despite numerous new therapeutic modalities to target various aspects of the tumor. There is a need to identify new, and even personalized, targetable GBM specific antigens. Our B-cell-based vaccine (BVax) is generated by isolating immune experienced B cells, identified by 4-1BBL, from murine secondary lymphoid organs or patient blood. We have shown this subset of B cells to have anti-tumoral potential in GBM. These cells are strengthened with BAFF, CD40, and IFNg stimulation to form BVax and then activated in vitro to form plasmablasts. Immunoprecipitation-mass spectrometry is performed using BVax-derived antibodies and tumor lysate from the paired patient specimen. We have identified unique antigens bound by BVax-derived antibodies. Given the significant therapeutic benefit we have seen using BVax-derived antibodies in preclinical murine models, we hypothesize that targeting these unique antigens would have significant therapeutic benefit in GBM patients. We focused on antigens that showed a survival benefit with lower expression using CGGA database analysis. We then confirm the presence and prevalence of the antigens within tumor cells in the patient’s tissue using immunohistochemistry, identifying some antigens in up to 15% of tumor cells. Using our brain tumor bank repository, we screened other GBM patient’s tissue for the presence of these markers to determine the broader applicability of targeting each antigen. We have identified proteins key in extracellular matrix formation which promote tumor growth and progression in cancer, including the ability to induce epithelial-mesenchymal transition. Simultaneously we have developed a computational algorithm to predict which antigens BVax-derived antibodies will bind using single cell RNA sequencing data from GBM patient-derived tumor and BVax, which may have broader applicability to a larger number of patients. Both techniques serve as exciting platforms to identify new therapeutic targets in GBM.
SURG-07. SURGICALLY TREATED BRAIN METASTASES FROM UTERINE ORIGIN: A CASE SERIES AND SYSTEMATIC REVIEW
Authors: Tiffany Eatz, Adam Levy, Laure Bystrom, Alexis Morell, Martin Merenzon, Dominique Higgins, Daniel Eichberg, Michael Kader, Manuela Guyot, Matthew Schlumbrecht, Nitesh Patel, Ashish Shah, Michael Silva, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Brain metastases from uterine origin have an incidence of 0.7-1.1%. Due to their rarity, there exists scarce literature entailing their neurosurgical treatment and outcomes. OBJECTIVE To report case management and outcomes of nine patients with brain metastases from uterine origin, as well as a systematic literature review findings focused on their neurosurgical treatment and outcomes. METHODS This study was divided into two parts: (1) a retrospective, single-center patient series assessing neurosurgical outcomes in patients with primary uterine cancer with brain metastases and (2) a systematic review of the literature between 1980 and 2021 assessing outcomes of patients with primary uterine cancer metastasized to the brain. RESULTS We report a case series at our single institution consisting of nine patients identified to have metastases to the brain from uterine origin that were treated with neurosurgical intervention. A total of 26 CNS lesions were identified among the 9 cases, with a mean number of lesions of 2.9 (1-7). The median age at the time of primary uterine cancer diagnosis was 49 years (26-80 years), with a median time from diagnosis to CNS metastasis of 19.5 months (3-54 months). The most common cerebral regions affected were the frontal lobe (42.3%) and the cerebellum (23%). Median progression free survival (PFS) and overall survival (OS) following intervention were 6.5 and 17.4 months, respectively. Stereotactic radiosurgery (SRS) alone resulted in the highest PFS and OS of 20.3 and 39 months, respectively. Sixteen studies were included in the systematic analysis. The mean OS was 13.3 months (3-41.1 months). CONCLUSION Brain metastases from uterine origin seem to most frequently result in multiple symptomatic lesions with additional concurrent metastasis to other organs. The most effective treatment modality appeared to be SRS alone. There is limited data on sole SRS treatment, so additional research regarding this modality is encouraged.
RADT-37. THE OUTCOMES OF INTRACRANIAL GERM CELL TUMOR PATIENTS WITH CHORIOCARCINOMA COMPONENT AND/OR Β-HCG HIGHER THAN 500IU/L UNDER RADIOTHERAPY-BASED TREATMENTS
Authors: Bo Li, Xiaoguang Qiu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In the previous studies, intracranial germ cell tumor (iGCTs) patients with pure choriocarcinoma or mixed germ cell tumors containing choriocarcinoma components showed similar dismal prognoses with median overall survival of 22 months and a one-year survival rate around 60%. However, those conclusions need update since radiotherapy, a milestone for this disease, was not applied to many patients in the published reports. Patients and METHODS Clinical data of iGCTs patients with histologically confirmed choriocarcinoma component and/or β-HCG &amp;gt; 500IU/L were collected from the archive of our institute and studied retrospectively. RESULTS Totally, 76 patients were eligible for the study. 11 patients took surgery as initial treatment, followed by chemoradiotherapy in terms of treatments. Sixty-one patients initiated their treatments with chemotherapy. Among them, twelve patients received second-look surgery due to residue disease. Subsequently, all received radiotherapy except for two early deaths. Four patients received radiotherapy initially, followed by chemotherapy. The median follow-up time was 63 months. The 5-year EFS and OS were 81.5% and 84.1%, respectively. Among patients who did not suffer from early death or progressed disease after induction chemotherapy (n = 68), multivariate analysis found chemotherapy cycles ( &amp;gt; 4 vs ≤ 4) (Hazard ratio [HR] for EFS 0.156, p = 0.021; HR for OS 0.110, p = 0.032), β-HCG level ( &amp;gt; 3000IU/L vs ≤ 3000IU/L) (HR for EFS 4.512, p = 0.052; HR for OS 6.604, p=0.028), and intertumoral hemorrhage (Yes vs No) (HR for EFS 23.177, p = 0.006; HR for OS 12.173, p = 0.081) were independent factors for survival. While radiation field (CSI vs non-CSI) was not proved to be a prognostic factor, either for EFS or OS. CONCLUSIONS iGCTs patients with choriocarcinoma component or β-HCG &amp;gt; 500IU/L showed improved survival with radiotherapy-based treatments. Patients with higher β-HCG levels and hemorrhage had a poorer prognosis. More chemotherapy cycles could bring additional survival benefits.
CNSC-28. IDENTIFICATION OF EAG2-KVß2 POTASSIUM CHANNEL COMPLEX IN NEURON-GBM COMMUNICATIONS REVEALS GBM VULNERABILITY TO DESIGNER INTERFERENCE PEPTIDE
Authors: Weifan Dong, Xin Chen, Xi Huang, Adam Fekete, Lu-yang Wang, Hongwei Liu
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas (GBMs) are the most aggressive brain tumors. GBM cells form extensive tumoral networks to communicate with each other and with surrounding neurons. Neuronal activity promotes GBM cell proliferation by secreting protumorigenic factors and triggering neuronal-activity-dependent Ca2+ transients, which are persisted and transmitted via tumor networks to promote overall tumor growth and therapy resistance. While how these processes are regulated is largely unknown. Here we show the GBM networks and Ca2+ transients are regulated by a voltage-gated potassium channel complex comprised of EAG2 and Kvβ2. GBM cells selectively overexpress Kvβ2 isoform 4 to facilitate tumor-specific Kvβ2-EAG2 interaction, which regulates neuron-GBM contact-dependent localization of EAG2. Rationally designed interfering peptide K90-114TAT blocks EAG2-Kvβ2 interaction, leading to reduced tumor cell proliferation, increased apoptosis, and prolonged survival of patient-derived xenograft mouse models with no evidence of toxicity to normal tissue. Single-cell RNA sequencing revealed a subgroup of GBM cells is highly sensitive to K90-114TAT treatment. These cells exhibit neuronal signatures and are highly associated with TMZ resistance and worse prognosis. In accordance with the notion, we found neurons promote TMZ resistance of GBM cells, which is regulated by the EAG2-Kvβ2 complex. Treating TMZ-resistant GBM xenograft mice with K90-114TAT yielded significant tumor burden reduction and prolonged survival. Together, our findings revealed the EAG2-Kvβ2 channel complex as a key regulator of neuron promoted GBM progression and designed an interfering peptide with anti-GBM efficacy and low general toxicity, which may have significant clinical impact.
RTID-01. ONC108: A RANDOMIZED PHASE 3 STUDY OF ONC201 IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA
Authors: Isabel Arrillaga-Romany, Andrew Lassman, Susan McGovern, Sabine Mueller, L Burt Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E Allen, Allen Melemed, Rohinton Tarapore, Dewen Yang, Patrick Y Wen, Timothy Cloughesy
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of objective response in ONC201-treated patients enrolled in one of five open-label trials has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ONC108 is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients will be randomized to receive once-weekly ONC201 or placebo following standard frontline radiotherapy. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed with the response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lanksy performance status ≥ 70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥ 10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible.
CTNI-43. COMBINATION OF TROFOSFAMIDE PLUS ETOPOSIDE IN RECURRENT ADULT-TYPE DIFFUSE GLIOMAS
Authors: Teresa Schmidt, Sarina Agkatsev, Jonas Feldheim, Christoph Oster, Tobias Blau, Ulrich Sure, Kathy Keyvani, Christoph Kleinschnitz, Martin Stuschke, Ken Hermann, Cornelius Deuschl, Björn Scheffler, Sied Kebir, Martin Glas, Lazaros Lazaridis
Journal: Neuro-Oncology (2022)

Abstract Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide (T/E) may be feasible in pediatric glioblastoma patients. We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) for a minimum of four weeks at the Division of Clinical Neurooncology at the University Hospital Essen. T/E was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy.A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n = 18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p = 0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p = 0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with T/E emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade III or higher) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n = 18, 86%; Lymphopenia: n=13, 62%). This study provides first indication that the combination of T/E is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
EXTH-60. ONCR-GBM, A NOVEL ARMED ONCOLYTIC HSV-1 VECTOR ENGINEERED FOR EFFICACY AND SAFETY IN GLIOBLASTOMA
Authors: Craig Strathdee, Federico Giovannoni, Martina Molgora, Lingxin Kong, Michael Floyd, Jian Teng, Yulia Gyulakian, Peter Grzesik, Terry Farkaly, Agnieszka Denslow, Sonia Feau, Judith Jacques, Edward Kennedy, Lorena Lerner, Christophe Quéva, Marco Colonna, Francisco Quintana
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common type of primary brain tumor in adults, with a 5-year overall survival of only 7%. Oncolytic viruses are a promising and active area of research in GBM with the recent approval of an oncolytic HSV-1 vector, teserpaturev (Delytact, also known as G47Δ, Daiichi Sankyo) for recurrent GBM based on an overall survival of 92% at 1 year. G207, an HSV-1 vector more attenuated than teserpaturev, recently reported acceptable tolerability with evidence of responses in children with recurrent or progressive high-grade glioma. These vectors are not expressing any cDNA transgene that may enhance and prolong antitumor activity. We report here the development of ONCR-GBM, an oncolytic HSV-1 vector specifically engineered for safety using a microRNA attenuation strategy to limit viral replication in healthy cell type of the CNS. ONCR-GBM has been developed from a novel potently oncolytic strain of HSV-1 and optimized for infection of GBM tumor cells. Antitumor efficacy has been further enhanced through the expression of multiple payloads designed to modify the immunosuppressive tumor microenvironment of GBM. We previously reported that a vector expressing IL-12 and a PD-1 antagonist nanobody achieved &amp;gt; 90% survival after a single injection in the GL261-Nectin1 orthotopic model. This vector promoted immune cell recruitment and activation in tumors and protected surviving animals from a subsequent tumor rechallenge. Additional payloads selected for interfering with the immune suppressive stroma in GBM have been evaluated for potentiating the response of IL-12 and anti PD-1 expressing HSV-1. We will present the outcome of the in vivo screen, and the selection of the optimal combination of payloads featured in ONCR-GBM clinical candidate.
TMIC-72. ALL-TRANS RETINOIC ACID INDUCES DURABLE TUMOR IMMUNITY IN IDH MUTANT GLIOMAS AND CIRCUMVENTS REPRESSION OF CRBP1-RETINOIC ACID AXIS
Authors: Xiaoran Zhang, Aparna Rao, Anthony Cillo, Arka Mallela, Katharine Krueger, Tullia Bruno, Nduka Amankulor
Journal: Neuro-Oncology (2022)

Abstract Diffuse gliomas are fatal, immunologically cold tumors characterized by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) genes. IDH mutations have been shown to result in global genomic hypermethylation and drastically altered transcriptomic landscape. We and others have shown that IDH mutation is direct responsible for the immunological cold landscape observed in IDH mutated glioma. Using a combination of animal models and patient-derived glioma stem cells (GSCs), we identify retinoic acid signaling as a primary regulator of innate and adaptive immune activation in IDHm gliomas. Using the Sleeping Beauty (SB) orthotopic murine model of IDH glioma, which faithfully recapitulates the TME seen in patients, we show that intracellular accumulation of oncometabolite 2-HG leads to hypermethylation and transcriptional repression of Retinol Binding Protein-1 (RBP1), which encode CRBP1, a key chaperone protein required for intracellular all-trans-retinoic-acid biosynthesis in glial cells. Restoration retinoic acid signaling through the addition of all-trans retinoic acid (ATRA) resulted in spontaneous tumor regression and prolonged survival. ATRA administration is further correlated with increased CD8, NK, M1 macrophages and decreased Treg and MDSC populations within the TME. Single-cell sequencing of the TME shows increased type I interferon signaling, myeloid cell polarization, T cell activation, and TCR diversity. Using knockdown and overexpression techniques in patient-derived GSCs, we show that CRBP1 activity is critical for NK mediated immune surveillance and cytotoxicity through regulation of NKG2D ligand expression and immune cell migration through differential regulation of CXCL12 and CCL2. In summary, epigenetic silencing of RBP1 by 2-HG induced hypermethylation leads to a global immune dysregulation resulting in an immunologically cold landscape. Restoration of retinoic acid signaling is a promising immunotherapeutic approach for the treatment of IDHm gliomas.
MODL-31. PHOTORECEPTOR-POSITIVE PROGENITORS PUTATIVE CELLS OF ORIGIN IN MYC-DRIVEN GROUP 3 MEDULLOBLASTOMA
Authors: Miao Zhao, Oliver Mainwaring, Gabriela Rosén, Thale Kristin Olsen, Sanne Rijpkema, Anders Sundström, Holger Weishaupt, Takahisa Furukawa, Fredrik Swartling
Journal: Neuro-Oncology (2022)

Abstract The cell of origin of Group 3 medulloblastoma, the most malignant medulloblastoma subgroup, is currently unknown and remains controversial. Transcriptional profiling has revealed that Group 3 medulloblastomas are characterized by elevated expression of a photoreceptor program, which has not been described in the normal cerebellar development but is well characterized in the developing retina and pineal gland. We used lineage tracing and single-cell sequencing to compare normal brain development with tumor development in our previously generated MYC-driven transgenic mouse model (GMYC), where mice spontaneously develop Group 3 medulloblastoma after 4-6 months of age. We found that tumor cells emerged from progenitor cells where MYC overexpression drove the transformation of immature progenitor cells with photoreceptor pathway activity. Our data suggest that MYC-driven Group 3 medulloblastoma originates from progenitor cells expressing a photoreceptor program, which has implications for future research and the development of novel treatments targeting this devastating childhood malignancy.
CTNI-23. PRELIMINARY SAFETY AND PHARMACOKINETICS DATA FOR A PHASE 1B TRIAL OF TELAGLENASTAT IN COMBINATION WITH RADIATION THERAPY AND TEMOZOLOMIDE IN PATIENTS WITH IDH-MUTANT GRADE 2/3 ASTROCYTOMA (NCI-10218)
Authors: Sani Kizilbash, David Piccioni, Solmaz Sahebjam, John Villano, Kurt Jaeckle, Mary Welch, Xiao-Tang Kong, Matthias Holdhoff, Anita Lammers, Adam Remick, Joel Reid, Jacob Allred, John Port, Ian Lanza, Samuel McBrayer, Charles Kunos, Geoffrey Shapiro, Alex Adjei
Journal: Neuro-Oncology (2022)

Abstract IDH mutant gliomas depend on glutaminase for glutamate/glutathione generation from glutamine because R-2-hydroxyglutarate inhibits branched chain amino acid transaminase mediated glutamate biosynthesis. Telaglenastat (CB-839 HCl) is a potent glutaminase-1 specific inhibitor which depletes tumor glutamate in orthotopic IDH mutant glioma PDX models and extends survival in these orthotopic models when added to radiation/temozolomide. NCI-10218 (NCT03528642) is a phase I clinical trial investigating the safety and tolerability of telaglenastat administered orally concurrently with standard doses of radiation (50.4 Gy, grade 2; 59.4 Gy, grade 3) and temozolomide (75 mg/m2 orally daily) in patients (age 16+) with previously untreated IDH mutant grade 2/3 astrocytoma. Telaglenastat dose was escalated in cohorts (400-800 mg twice daily) based on a standard 3 + 3 design to determine the recommended phase 2 dose (RP2D). Toxicities were graded per CTCAE v5.0. An expansion cohort additionally incorporated a seven-day run-in of telaglenastat monotherapy at RP2D prior to radiation to evaluate the pharmacodynamic impact of telaglenastat on plasma and tumor metabolites. 23 patients with IDH mutant astrocytoma (WHO grade 2, n = 5; WHO grade 3, n = 18) were accrued between December 2018 and January 2022 (Dose Escalation: 16; Dose Expansion: 7). Median age was 32 years (range 23-69 years). 61% were male and 70% were ECOG 0. No dose-limiting toxicities were observed. Grade 3/4 adverse events (independent of attribution) included: lymphopenia (3), neutropenia (2), leukocytosis (2), alanine transaminase elevation (2), thrombocytopenia (1), leukopenia (1), maculopapular rash (1), hyperglycemia (1), hyponatremia (1). The RP2D of concurrent telaglenastat was defined as 800 mg twice daily. Following peak absorption on Day 15 at RP2D, the mean (%CV) terminal elimination half-life in the plasma was 4.2 (53.5%) hours (range 2.1-7.1 hours). The Cmax, Tmax, oral clearance, and AUC were 1496 ng/mL, 4.0 hr, 93.6 L/hr/m2, and 7430 ng/mL*hr, respectively.